The broad aim of the proposed project is to improve the quality of antihypertensive drug therapy in the elderly. There are between 6 and 9 million hypertensives aged more than 65 years in the United States. Effective therapy protects the elderly from the excess cardiovascular morbidity and mortality related to their hypertension. Conversely, inappropriate therapy is particularly likely to cause adverse effects within this age group. The elderly differ from younger age groups in both the disposition of and response to a range of drugs. In addition, the hemodynamic profile of hypertension changes with aging. Despite this, the responsiveness of the elderly to antihypertensive drugs has not been studied in detail. The elderly are less likely than younger hypertensives to respond to propranolol, frequently used as a step two drug in the stepped care approach to the therapy of hypertension. Recommendations have, therefore, been made that vasodilator agents be used in the elderly as step two drugs. The proposed studies will provide the data to validate or refute this recommendation. Studies will examine the effect of age on the responsiveness to widely used antihypertensive agents with differing sites of action, nitroprusside, hydralazine and clonidine. There are three major determinants of hypotensive response to a drug; the pharmacokinetics of the drug, target organ sensitivity to the drug and the extent of homeostatic response to the hypotensive effect. The components of hypotensive responsiveness will be individually examined for these drugs in hypertensive patients of a wide range of ages. This will be done by defining in detail the pharmacokinetics of hydralazine and clonidine using specific, highly sensitive assay techniques. Drug doses, drug concentrations and plasma catecholamine levels (a measure of sympathetic activity) will be related to a range of hemodynamic parameters. The information gained will be used to make therapeutic recommendations for the elderly hypertensive with regard to the drugs studied.